Spastic paraplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonal transport in a Drosophila HSP model.
Spastic paraplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonal transport in a Drosophila HSP model.
复制标题
DOI：
10.1371/journal.pgen.1003066
复制
发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Rasse TM
中科院分区：
文献类型：
--
作者：
Füger P;Sreekumar V;Schüle R;Kern JV;Stanchev DT;Schneider CD;Karle KN;Daub KJ;Siegert VK;Flötenmeyer M;Schwarz H;Schöls L;Rasse TM
遗传性痉挛性截瘫（HSPs）包括一组以下肢痉挛性无力为特征的遗传异质性神经退行性疾病。我们已经建立了由KIF5A突变引起的10型热休克蛋白（SPG10）的果蝇模型。KIF5A编码神经元微管运动蛋白-1的重链。我们的研究结果表明，SPG10不是由单倍不足引起的，而是由突变体KIF5A对激酶1复合物的选择性显性负作用导致内源性激酶1功能的丧失引起的。我们没有发现任何证据表明突变的激酶蛋白重链（Khc）或受影响的激酶蛋白-1复合物具有额外的、更广泛的毒性。携带人类spg10相关突变（N256S）的果蝇Khc异位表达足以干扰轴突运输并诱导果蝇运动神经元疾病。最近发现的与SPG10疾病表现有关的神经丝在节肢动物中不存在。因此，不同于神经丝的运动蛋白-1转运受损足以引起热休克样病理改变，如轴突肿胀、突触结构和功能改变、行为缺陷和死亡率增加。遗传性痉挛性截瘫（HSPs）包括一组遗传性神经系统疾病。HSP的主要特征是由于神经细胞功能障碍导致下肢进行性僵硬。我们研究了由神经元运动蛋白KIF5A突变引起的HSP 10型。HSP 10型以常染色体显性方式遗传，这意味着患者具有正常和突变的KIF5A基因拷贝。KIF5A在神经元功能中发挥重要作用：它将货物运输到距离细胞体1米远的突触。我们使用果蝇作为模型来研究突变在KIF5A中的作用。我们的苍蝇模型复制了热休克的一个核心特征：由具有长细胞过程的神经细胞激活的肌肉受损更严重。我们现在讨论为什么一个突变的KIF5A拷贝足以引起热休克。迄今为止，人们一直认为患者患有HSP可能是因为KIF5A功能不足或突变的KIF5A干扰了正常KIF5A的功能。我们为后一种可能性提供了证据。
Hereditary spastic paraplegias (HSPs) comprise a group of genetically heterogeneous neurodegenerative disorders characterized by spastic weakness of the lower extremities. We have generated a Drosophila model for HSP type 10 (SPG10), caused by mutations in KIF5A. KIF5A encodes the heavy chain of kinesin-1, a neuronal microtubule motor. Our results imply that SPG10 is not caused by haploinsufficiency but by the loss of endogenous kinesin-1 function due to a selective dominant-negative action of mutant KIF5A on kinesin-1 complexes. We have not found any evidence for an additional, more generalized toxicity of mutant Kinesin heavy chain (Khc) or the affected kinesin-1 complexes. Ectopic expression of Drosophila Khc carrying a human SPG10-associated mutation (N256S) is sufficient to disturb axonal transport and to induce motoneuron disease in Drosophila. Neurofilaments, which have been recently implicated in SPG10 disease manifestation, are absent in arthropods. Impairments in the transport of kinesin-1 cargos different from neurofilaments are thus sufficient to cause HSP–like pathological changes such as axonal swellings, altered structure and function of synapses, behavioral deficits, and increased mortality. Hereditary spastic paraplegias (HSPs) comprise a group of inherited neurological diseases. The main feature of HSP is progressive stiffness of the lower limbs due to a dysfunction of nerve cells. We study HSP type 10, which is caused by mutations in the neuronal motor protein KIF5A. HSP type 10 is inherited in an autosomal-dominant manner, which means that patients have a normal and a mutated copy of the KIF5A gene. KIF5A plays an important role in neuronal function: it transports cargos to the synapse that can be up to 1 m from the cell body. We use the fruit fly as a model to investigate the role of mutations in KIF5A. Our fly model replicates a central feature of HSP: muscles that are activated by nerve cells that have long cellular processes are more severely impaired. We now address why one mutated copy of KIF5A is sufficient to cause HSP. To date, it has been thought that patients might have HSP because they have insufficient functional KIF5A or because mutated KIF5A disturbs the function of normal KIF5A. We provide evidence for the latter possibility.
登录
查看更多内容
影响因子：
12.4
作者：
Fan, Y.;Bergmann, A.
通讯作者：
Bergmann, A.
影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
DOI：
10.1083/jcb.200908075
发表时间：
2009-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ally S;Larson AG;Barlan K;Rice SE;Gelfand VI
通讯作者：
Gelfand VI
DOI：
10.1038/nrn2946
发表时间：
2011-01
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Blackstone C;O'Kane CJ;Reid E
通讯作者：
Reid E
影响因子：
3.5
作者：
Ebbing, Bettina;Mann, Klaudiusz;Woehlke, Guenther
通讯作者：
Woehlke, Guenther